Circadian rhythms: The cancer connection
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so patient commitment to safe sex practices will be an important adjunct to STI. It is not clear whether superinfection is only a risk during treatment interruption: more studies on this are needed. Altfeld et al.’s work 1 is a beautiful illustra- tion of the power of modern techniques to explore the minute details of a virus-specific immune response. But the effort required will preclude studies of large numbers of patients. Certainly, this single-patient analy- sis raises many questions, but whether the news is bad, neutral or even good remains to be seen. Although causing a brief pause for thought, nothing here should slow or divert efforts to develop an HIV vaccine. ■ Andrew J. McMichael and Sarah L. Rowland-Jones are at the MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. e-mails: andrew.mcmichael@clinical- medicine.oxford.ac.uk sarah.rowland-jones@clinical- medicine.oxford.ac.uk 1. Altfeld, M. et al. Nature 420, 434–439 (2002). 2. Rosenberg, E. S. et al. Nature 407, 523–526 (2000). 3. Long, E. M. et al. Nature Med. 6, 71–75 (2000). 4. Schmitz, J. E. et al. Science 283, 857–860 (1999). 5. Klenerman, P., Wu, Y. & Phillips, R. Curr. Opin. Microbiol. 5, 408–413 (2002). 6. Rowland-Jones, S. L. et al. J. Clin. Invest. 102, 1758–1765 (1998). 7. Amara, R. R. et al. Science 292, 69–74 (2001). 8. Jost, S. et al. New Engl. J. Med. 347, 731–736 (2002). 9. Daniel, M. D. et al. Science 258, 1938–1941 (1992). 10. Douek, D. C. et al. Nature 417, 95–98 (2002). 11.Appay, V. et al. J. Exp. Med. 192, 63–75 (2000). 12. Gallimore, A. et al. J. Exp. Med. 187, 1647–1657 (1998). 13. Ferrari, G. et al. Immunol. Lett. 79, 37–45 (2001). 14. Kaul, R. et al. J. Clin. Invest. 107, 1303–1310 (2001). 15.Vogel, T. U. et al. J. Immunol. 169, 4511–4521 (2002). 16. Oxenius, A. et al. Proc. Natl Acad. Sci. USA 99, 13747–13752 (2002). I f the mantra in real estate is ‘location, location, location’, in genetics it would be ‘phenotype, phenotype, phenotype’. There is simply no substitute for a detailed pheno- typic analysis of a mutant strain (study of the overt manifestation of a mutated gene in the organism). This has the potential to reveal unanticipated — and sometimes truly surprising — relationships between geno- type and phenotype, or between a primary phenotype and a secondary one. Such was the case for an analysis published recently in Cell by Lee and colleagues 1 . The organisms under study here were mice in which both copies of the mPer2 gene were mutated — a genotype shown previ- ously 2 to cause a strong defect in circadian rhythms. Most organisms have endogenous ‘clocks’ that control rhythms of physiology and behaviour with roughly 24-hour (circa- dian) periodicity. But the period is short- ened, and rhythmicity is lost, in the mPer2 mutant mice. This is reminiscent of the effects of the original perS or per0 mutations in fruitflies, described in the 1971 landmark paper from Konopka and Benzer 3 . By observing their mutant mice for a couple of years, however, Lee and colleagues 1 made an unexpected discovery: the animals were unusually cancer prone. At six months of age they began to show excessive cell proliferation in the salivary glands, as well as teratomas — tumours that originate from germ cells and comprise a mix of cell types. Thirty per cent of the mutant mice died before the age of 16 months, half of these from spontaneous lymphomas. In contrast, such lymphomas were first found in normal mice at the age of 20 months, a highly significant difference. The mutant animals were also more sensitive to g-radiation, as indicated by premature hair greying and hair loss, and an increased rate of tumour forma- tion — this last effect stemming, at least in part, from a decreased likelihood of cell death (apoptosis) in response to radiation. So, what could be the story here? The current picture of the central circadian clock in animals is of a self-sustaining transcrip- tion–translation feedback loop, involving the transcription of key clock genes, their translation into protein, and the proteins’ repression of transcription of the same key genes 4 (as well as of downstream, clock-con- trolled genes). In fact, given the importance of post-translational mechanisms — such as protein phosphorylation and turnover — and the lack of translational control in the current picture, it might be more accurate to describe it as a macromolecular feedback loop. In any case, the mPer2 protein is a key clock component: it contributes to the circadian regulation of transcription of both mPer2 and downstream genes 5 . All of which begs the question: is there a tight relationship between g-radiation and clock genes? And could disruption of circadian transcriptional regulation cause the defects in cell proliferation and death (together termed cell growth) seen even in the absence of g-radiation in mPer2 mutant mice? In other words, is there a transcription- al cascade from clock genes, to downstream growth-control genes, to growth-effector genes? The answers all appear to be yes. Lee and colleagues’ results show that, in normal mice, the expression of several core clock genes was rapidly and potently upregu- lated in the liver in response to g-radiation. But in the mutants this response was absent or severely attenuated. Even more surprising was the authors’ analysis of a few key genes concerned with cell growth. They found that expression of the Myc gene, as judged by levels of its messenger RNA, was circadian in wild-type liver; but in the mutants the expression pattern was modestly shifted and levels of Myc mRNA were dramatically increased. Moreover, experiments in cul- tured cells suggested that Myc transcription is directly regulated by the circadian clock. The authors also looked at the expression of cyclin D1 and Gadd45a, two Myc-regulated mRNAs, and found that the levels of both fluctuated in a circadian pattern in wild- type livers; in the mutants, both patterns were altered. So Lee and colleagues propose that the key effect of inactivating mPer2 is to de- repress Myc expression, leading to excessive cell growth and tumour formation. The effect is exacerbated by g-radiation, which normally upregulates clock genes and there- by presumably leads to Myc repression. This fails in the mPer2 mutants. If these proposals are true, there are some testable predictions. First, overexpresssing Myc in an otherwise normal genetic background should have the same growth-promoting effects as mutating mPer2. Second, and more important, inhibiting Myc expression should suppress tumour formation in mPer2 mutants. One caveat is that all of these experiments were performed under conditions of 12 hours’ light, 12 hours’ darkness, so it could be that the mRNA cycles were merely light- driven, not clock-driven. In this context, it is notable that Myc and Gadd45a were not identified as cycling genes (although cyclin D1 was) in three out of four microarray studies of liver mRNAs 6–9 . But the marked effects of the mPer2 mutation suggest that, at the very least, there is a strong connection between cell growth and the circadian clock. The discrepancy also reinforces the impor- tance of taking microarray data — especially negative data — with a pinch of salt. In our opinion, careful biochemical analyses are more credible. More generally, the new results 1 have brought into proximity two previously dis- parate fields of study: circadian rhythms and cell-growth control. One reason why they have hitherto been infrequent bedfellows is that the mammalian circadian rhythm field has historically focused on the brain and, more narrowly, on the suprachiasmatic nucleus — the region of the hypothalmus that is essential for directing cycles of loco- news and views NATURE | VOL 420 | 28 NOVEMBER 2002 | www.nature.com/nature 373 Circadian rhythms The cancer connection Michael Rosbash and Joseph S. Takahashi The Per2 gene is a core component of the circadian clock in mammals. It now seems that the mouse Per2 gene is also involved in suppressing tumours, through other genes that affect cell proliferation and death. © 2002 Nature Publishing Group
Transcript of Circadian rhythms: The cancer connection
so patient commitment to safe sex practiceswill be an important adjunct to STI. It is notclear whether superinfection is only a riskduring treatment interruption: more studieson this are needed.
Altfeld et al.’s work1 is a beautiful illustra-tion of the power of modern techniques toexplore the minute details of a virus-specificimmune response. But the effort requiredwill preclude studies of large numbers ofpatients. Certainly, this single-patient analy-sis raises many questions, but whether thenews is bad, neutral or even good remains tobe seen. Although causing a brief pause forthought, nothing here should slow or divertefforts to develop an HIV vaccine. ■
Andrew J. McMichael and Sarah L. Rowland-Jonesare at the MRC Human Immunology Unit,Weatherall Institute of Molecular Medicine,
John Radcliffe Hospital, Oxford OX3 9DS, UK.e-mails: andrew.mcmichael@clinical-medicine.oxford.ac.uksarah.rowland-jones@clinical-medicine.oxford.ac.uk1. Altfeld, M. et al. Nature 420, 434–439 (2002).
2. Rosenberg, E. S. et al. Nature 407, 523–526 (2000).
3. Long, E. M. et al. Nature Med. 6, 71–75 (2000).
4. Schmitz, J. E. et al. Science 283, 857–860 (1999).
5. Klenerman, P., Wu, Y. & Phillips, R. Curr. Opin. Microbiol. 5,408–413 (2002).
6. Rowland-Jones, S. L. et al. J. Clin. Invest. 102, 1758–1765 (1998).
7. Amara, R. R. et al. Science 292, 69–74 (2001).
8. Jost, S. et al. New Engl. J. Med. 347, 731–736 (2002).
9. Daniel, M. D. et al. Science 258, 1938–1941 (1992).
10.Douek, D. C. et al. Nature 417, 95–98 (2002).
11.Appay, V. et al. J. Exp. Med. 192, 63–75 (2000).
12.Gallimore, A. et al. J. Exp. Med. 187, 1647–1657 (1998).
13.Ferrari, G. et al. Immunol. Lett. 79, 37–45 (2001).
14.Kaul, R. et al. J. Clin. Invest. 107, 1303–1310 (2001).
15.Vogel, T. U. et al. J. Immunol. 169, 4511–4521 (2002).
16.Oxenius, A. et al. Proc. Natl Acad. Sci. USA 99, 13747–13752
(2002).
If the mantra in real estate is ‘location, location, location’, in genetics it would be‘phenotype, phenotype, phenotype’. There
is simply no substitute for a detailed pheno-typic analysis of a mutant strain (study of the overt manifestation of a mutated gene in the organism). This has the potential toreveal unanticipated — and sometimes trulysurprising — relationships between geno-type and phenotype, or between a primaryphenotype and a secondary one. Such was thecase for an analysis published recently in Cellby Lee and colleagues1.
The organisms under study here weremice in which both copies of the mPer2 genewere mutated — a genotype shown previ-ously2 to cause a strong defect in circadianrhythms. Most organisms have endogenous‘clocks’ that control rhythms of physiologyand behaviour with roughly 24-hour (circa-dian) periodicity. But the period is short-ened, and rhythmicity is lost, in the mPer2mutant mice. This is reminiscent of theeffects of the original perS or per0 mutationsin fruitflies, described in the 1971 landmarkpaper from Konopka and Benzer3.
By observing their mutant mice for a couple of years, however, Lee and colleagues1
made an unexpected discovery: the animalswere unusually cancer prone. At six monthsof age they began to show excessive cell proliferation in the salivary glands, as well as teratomas — tumours that originate fromgerm cells and comprise a mix of cell types.Thirty per cent of the mutant mice diedbefore the age of 16 months, half of these
from spontaneous lymphomas. In contrast,such lymphomas were first found in normalmice at the age of 20 months, a highly significant difference. The mutant animalswere also more sensitive to g-radiation, asindicated by premature hair greying and hairloss, and an increased rate of tumour forma-tion — this last effect stemming, at least inpart, from a decreased likelihood of celldeath (apoptosis) in response to radiation.
So, what could be the story here? The current picture of the central circadian clockin animals is of a self-sustaining transcrip-tion–translation feedback loop, involvingthe transcription of key clock genes, theirtranslation into protein, and the proteins’repression of transcription of the same keygenes4 (as well as of downstream, clock-con-trolled genes). In fact, given the importanceof post-translational mechanisms — such asprotein phosphorylation and turnover —and the lack of translational control in thecurrent picture, it might be more accurate to describe it as a macromolecular feedbackloop. In any case, the mPer2 protein is a key clock component: it contributes to thecircadian regulation of transcription of bothmPer2 and downstream genes5.
All of which begs the question: is there a tight relationship between g-radiation and clock genes? And could disruption of circadian transcriptional regulation causethe defects in cell proliferation and death(together termed cell growth) seen even inthe absence of g-radiation in mPer2 mutantmice? In other words, is there a transcription-
al cascade from clock genes, to downstreamgrowth-control genes, to growth-effectorgenes? The answers all appear to be yes.
Lee and colleagues’ results show that, innormal mice, the expression of several coreclock genes was rapidly and potently upregu-lated in the liver in response to g-radiation.But in the mutants this response was absentor severely attenuated. Even more surprisingwas the authors’ analysis of a few key genesconcerned with cell growth. They found thatexpression of the Myc gene, as judged by levels of its messenger RNA, was circadian in wild-type liver; but in the mutants the expression pattern was modestly shifted and levels of Myc mRNA were dramaticallyincreased. Moreover, experiments in cul-tured cells suggested that Myc transcription is directly regulated by the circadian clock.The authors also looked at the expression ofcyclin D1 and Gadd45a, two Myc-regulatedmRNAs, and found that the levels of both fluctuated in a circadian pattern in wild-type livers; in the mutants, both patterns were altered.
So Lee and colleagues propose that thekey effect of inactivating mPer2 is to de-repress Myc expression, leading to excessivecell growth and tumour formation. Theeffect is exacerbated by g-radiation, whichnormally upregulates clock genes and there-by presumably leads to Myc repression. Thisfails in the mPer2 mutants. If these proposalsare true, there are some testable predictions.First, overexpresssing Myc in an otherwisenormal genetic background should have thesame growth-promoting effects as mutatingmPer2. Second, and more important,inhibiting Myc expression should suppresstumour formation in mPer2 mutants.
One caveat is that all of these experimentswere performed under conditions of 12hours’ light, 12 hours’ darkness, so it couldbe that the mRNA cycles were merely light-driven, not clock-driven. In this context, it is notable that Myc and Gadd45a were notidentified as cycling genes (although cyclinD1 was) in three out of four microarray studies of liver mRNAs6–9. But the markedeffects of the mPer2 mutation suggest that, atthe very least, there is a strong connectionbetween cell growth and the circadian clock.The discrepancy also reinforces the impor-tance of taking microarray data — especiallynegative data — with a pinch of salt. In ouropinion, careful biochemical analyses aremore credible.
More generally, the new results1 havebrought into proximity two previously dis-parate fields of study: circadian rhythms andcell-growth control. One reason why theyhave hitherto been infrequent bedfellows isthat the mammalian circadian rhythm fieldhas historically focused on the brain and,more narrowly, on the suprachiasmaticnucleus — the region of the hypothalmusthat is essential for directing cycles of loco-
news and views
NATURE | VOL 420 | 28 NOVEMBER 2002 | www.nature.com/nature 373
Circadian rhythms
The cancer connectionMichael Rosbash and Joseph S. Takahashi
The Per2 gene is a core component of the circadian clock in mammals. It now seems that the mouse Per2 gene is also involved in suppressingtumours, through other genes that affect cell proliferation and death.
© 2002 Nature Publishing Group
motor activity. Most adult neurons do notdivide yet manifest potent molecularrhythms, suggesting that these rhythms arecontrolled separately from cell division. Asimilar conclusion stems from work on ratfibroblast cells, where molecular rhythmspersist even if cell division is blocked10. Andclassical work in microbes indicates thatrapid cell division can be completely un-coupled from the 24-hour timing of the circadian system in the same cells11.
On the other hand, cell division inmicrobes can be driven by the circadian cyclewhen the periodicity of division is not farfrom 24 hours. This suggests that the circa-dian system is important for proper growthcontrol, and is consistent with the apparentcircadian regulation of cell proliferation and apoptosis1. Moreover, the striking time-dependent response of wild-type miceto g-radiation1 reinforces the potentialimportance of circadian principles in cancerand cancer therapies. It seems that cancercan be a direct consequence of the absence of circadian regulation. Perhaps this appliesto other diseases, too. For instance, shift
workers tend to have increased health prob-lems. These could result indirectly from disruption of physiological systems that areunder circadian control — but there mightalso be a direct connection to the clock. ■
Michael Rosbash is at the Howard Hughes MedicalInstitute, Department of Biology, BrandeisUniversity, Waltham, Massachusetts 02454, USA.e-mail: [email protected] S. Takahashi is at the Howard HughesMedical Institute, Department of Neurobiology andPhysiology, Northwestern University, Evanston,Illinois 60208, USA.e-mail: [email protected]. Fu, L., Pelicano, H., Liu, J., Huang, P. & Lee, C. C. Cell 111,
41–50 (2002).
2. Zheng, B. H. et al. Nature 400, 169–173 (1999).
3. Konopka, R. J. & Benzer, S. Proc. Natl Acad. Sci. USA 68,
2112–2116 (1971).
4. Allada, R., Emery, P., Takahashi, J. S. & Rosbash, M.
Annu. Rev. Neurosci. 24, 1091–1119 (2001).
5. Zheng, B. H. et al. Cell 105, 683–694 (2001).
6. Akhtar, R. A. et al. Curr. Biol. 12, 540–550 (2002).
7. Panda, S. et al. Cell 109, 307–320 (2002).
8. Storch, K. F. et al. Nature 417, 78–83 (2002).
9. Ueda, H. R. et al. Nature 418, 534–539 (2002).
10.Balsalobre, A., Damiola, F. & Schibler, U. Cell 93, 929–937 (1998).
11. Johnson, C. H. & Golden, S. S. Annu. Rev. Microbiol. 53,
389–409 (1999).
tion as the highest-energy magnet to its highmagnetization (mainly from Fe ions) and toits tetragonal structure and Nd ions, whichtogether produce a high degree of magneticanisotropy. This anisotropy in turn causeshigh coercivity.
Is there hope of raising the maximumenergy product observed to values approach-ing the upper bound of 144 MGOe? Despitestrenuous efforts, a compound with the nec-essary properties has eluded researchers. But,about a decade ago, an idea emerged thatbrought new hope. This is the concept of‘exchange coupling’ between a hard (high-coercivity) material and a soft (low-coerci-vity) material with a large magnetization. In a two-phase mixture of such materials,exchange forces between the phases meanthat the resulting magnetization and coerci-vity of the material will be some average ofthe properties of the two constituent phases4.But for the exchange coupling to be effective,the relative sizes of the grains of the two materials must be chosen carefully: Knellerand Hawig5 showed that the characteristicdimensions of the soft phase cannot exceedabout twice the wall thickness of magneticdomains in the hard phase. Typically, thislimits the soft phase to grains of about 10-nmdiameter. Similarly, the hard phase must havedimensions of this order or the volume frac-tion of the soft phase will be rather low, thuslimiting the magnetization of the composite.
Skomski and Coey4 showed that in anideal exchange-coupled magnet, consistingof aligned grains of Sm2Fe17N3 and Fe65Co35,the theoretical upper bound on the energyproduct is about 125 MGOe. But in the real world, attempts to fabricate two-phase nanostructures with a high energyproduct have had only limited success. Bulkmagnets produced by subjecting the two-phase material to ultra-fast cooling and thenannealing, or by mechanical milling, havenot achieved energy products beyond about20 MGOe (ref. 6). There are several diffi-culties to be overcome: controlling the material structure at the nanoscale, espe-cially to create uniform grain sizes of about 10 nm; aligning the hard grains sufficiently;and ensuring effective exchange coupling between the two phases in all grains througha homogeneous distribution.
In fact, higher energy products have been obtained in thin-film materials7 basedon iron–platinum compounds. In these,perpendicular anisotropy (and hence highcoercivity) is achieved by first preparingnanoscale Fe–Pt multilayers, and thenapplying a specific thermal processing tech-nique. Unfortunately, however, this tech-nique is not appropriate for making practi-cal bulk magnets. All in all, the work so farhas shown the nanostructuring challengesto be formidable.
But now Zeng et al.1 have devised amethod of chemical synthesis with the
news and views
Applied physics
Strong magnets by self-assemblyDavid J. Sellmyer
Newly developed nanomaterials are proving useful in many fields, butmaterials that make strong permanent magnets are difficult to devise.Progress has been made using a self-assembled mixture of nanoparticles.
Controlled structuring of materials atthe nanoscale can enhance some oftheir properties and widen their range
of applications. Magnetic materials, such asrecording media, field sensors and memorydevices, are advancing rapidly in terms oftheir miniaturization, sensitivity and otherfigures of merit. But progress in producingpermanent magnets has been limited by thedifficulty of finding new compounds withthe necessary properties. On page 395 of thisissue, Zeng et al.1 show how self-assembly ofmixtures of magnetic nanoparticles makes itpossible to fabricate materials with excellentmagnetic properties. The process of chemi-cal synthesis and the resulting nanostruc-tures, with magnetic coupling betweennanoscale grains in the composite material,are impressive.
The figure of merit by which permanent-magnet materials are judged is the energyproduct — a measure of the maximum magnetostatic energy that would be stored in free space between the pole pieces of amagnet made from the material in question2.The energy product depends on the area of the ‘hysteresis loop’ (Fig. 1). A typical hysteresis loop arises from plotting the magnetization of the material as the applied
magnetic field is varied — the response of the materials follows two distinct paths onmagnetization and demagnetization. As wellas the saturation point (maximum magneti-zation), the hysteresis loop is characterizedby the ‘coercivity’ of the material, which isthe reverse-field strength needed to reducethe flux density to zero. To obtain a largeenergy product requires large magnetizationand large coercivity.
The largest room-temperature magneti-zation for a material — a Fe65Co35 alloy —corresponds to an internal flux density ormagnetic induction of about 24 kilogauss.Theoretically, the upper bound on the energyproduct for the material (proportional to thesaturation magnetization squared) is 144MGOe, for induction measured in gauss (G)and field in oersted (Oe). But in practice, theFe–Co alloy does not have such a large energyproduct because it is a soft magnet — that is, its coercivity is actually fairly low and asmall reverse field is sufficient to reduce themagnetization to zero.
The largest energy product observed innature, for the compound Nd2Fe14B, is 56.7MGOe (ref. 3). Nd2Fe14B has a complexstructure containing 68 atoms in its unit cell.The Nd–Fe–B class of magnets owes its posi-
374 NATURE | VOL 420 | 28 NOVEMBER 2002 | www.nature.com/nature© 2002 Nature Publishing Group
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